Renoprotective effects of crocin against colistin-induced nephrotoxicity in a rat model

Document Type : Original Article

Authors

1 Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran

2 Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran

3 Targeted Drug Delivery Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran

Abstract

Objective(s): Colistin is used to treat multidrug-resistant gram-negative bacterial infections. It increases the membrane permeability of kidney cells, leading to kidney toxicity. Crocin, a carotenoid found in saffron, has anti-oxidant and nephroprotective properties. The present study aimed to explore the potential renoprotective effects of crocin against colistin-induced nephrotoxicity.
Materials and Methods: Six groups of male Wistar rats were utilized: 1- Control (0.5 ml of normal saline, 10 days, IP); 2- Crocin (40 mg/kg, 10 days, IP); 3-Colistin (23 mg/kg, 7 days, IP); 4-6 Colistin (23 mg/kg, 7 days, IP)+ crocin (10, 20, 40 mg/kg, 10 days, IP). On day 11, rats were sacrificed and their blood and kidney samples were collected to measure creatinine, blood urea nitrogen (BUN), glutathione (GSH) levels, malondialdehyde (MDA), and histopathological alterations.
Results: Colistin caused a significant increase in BUN, creatinine, and MDA, and a decrease in GSH compared to the control group. It also led to congested blood vessels, glomerular shrinkage, and medullary tubular degeneration. Co-administration of crocin with colistin resulted in a significant decrease in BUN and creatinine, increased GSH levels, and ameliorated the histopathological alterations compared to the colistin group. No significant difference was found between the control group and the crocin (40 mg/kg) group.
Conclusion: It might be suggested that colistin can induce kidney damage by inducing oxidative stress. However, crocin shows protective effects against colistin-induced renal injury by acting as an anti-oxidant. Hence, crocin can be used as a supplement to reduce tissue and biochemical damage caused by colistin injection.

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Main Subjects


1. Falagas ME, Kasiakou SK, Saravolatz LD. Colistin: The revival of polymyxins for the management of multidrug-resistant Gram-negative bacterial infections. Clin Infect Dis 2005; 40:1333-1341.
2. Gai Z, Samodelov SL, Kullak-Ublick GA, Visentin M. Molecular mechanisms of colistin-induced nephrotoxicity. Molecules 2019; 24:653-666.
3. Aggarwal R, Dewan A. Comparison of nephrotoxicity of Colistin with Polymyxin B administered in currently recommended doses: a prospective study. Ann Clin Microbiol Antimicrob 2018; 17:15-22.
4. Oktan MA, Heybeli C, Ural C, Kocak A, Bilici G, Cavdar Z, et al. Alpha-lipoic acid alleviates colistin nephrotoxicity in rats. Hum Exp Toxicol 2021; 40:761-771.
5. Ozkan G, Ulusoy S, Orem A, Alkanat M, Mungan S, Yulug E, et al. How does colistin-induced nephropathy develop and can it be treated? Antimicrob Agents Chemother 2013; 57:3463-3469.
6. Dai C, Wang Y, Sharma G, Shen J, Velkov T, Xiao X. Polymyxins-curcumin combination antimicrobial therapy: Safety implications and efficacy for infection treatment. Anti-oxidants 2020; 9:506-523.
7. Wang J, Ishfaq M, Fan Q, Chen C, Li J. 7-hydroxycoumarin attenuates colistin-induced kidney injury in mice through the decreased level of histone deacetylase 1 and the activation of Nrf2 signaling pathway. Front Pharmacol 2020; 11:1146-1175.
8. Yavuz YC, Cetin N, Menevşe E, Cizmecioglu A, Celik E, Biyik Z, et al. Can magnesium sulfate prophylaxis reduce colistin nephrotoxicity? Nefrologia 2021; 41:661-669.
9. Dumludag B, Derici MK, Sutcuoglu O, Ogut B, Pasaoglu OT, Gonul II, et al. Role of silymarin (Silybum marianum) in the prevention of colistin-induced acute nephrotoxicity in rats. Drug Chem Toxicol 2022; 45:568-575.
10. Rana MA, Arshad MN, Siddiqui SS, Nasiruddin M. Study of effect of Nigella sativa on prevention of nephrotoxicity induced by colistin in experimental animals. Int J Basic Clin Pharmacol 2019; 8:306-311.
11. Ghasemzadeh Rahbardar M, Hosseinzadeh H. A review of how the saffron (Crocus sativus) petal and its main constituents interact with the Nrf2 and NF-κB signaling pathways. Naunyn Schmiedebergs Arch Pharmacol 2023; 396:1879-1909.
12. Hosseini A, Razavi BM, Hosseinzadeh H. Pharmacokinetic properties of saffron and its active components. Eur J Drug Metab Pharmacokinet 2018; 43:383-390.
13. Zilaee M, Hosseini SA, Jafarirad S, Abolnezhadian F, Cheraghian B, Namjoyan F, et al. An evaluation of the effects of saffron supplementation on the asthma clinical symptoms and asthma severity in patients with mild and moderate persistent allergic asthma: a double-blind, randomized placebo-controlled trial. Respir Res 2019; 20:1-11.
14. Vafaeipour Z, Ghasemzadeh Rahbardar M, Hosseinzadeh H. Effect of saffron, black seed, and their main constituents on inflammatory cytokine response (mainly TNF-α) and oxidative stress status: an aspect on pharmacological insights. Naunyn Schmiedebergs Arch Pharmacol 2023.
15. Zeinali M, Zirak MR, Rezaee SA, Karimi G, Hosseinzadeh H. Immunoregulatory and anti-inflammatory properties of Crocus sativus (Saffron) and its main active constituents: A review %J Iranian Journal of Basic Medical Sciences.  2019; 22:334-344.
16. Boskabady MH, Ghasemzadeh Rahbardar M, Nemati H, Esmaeilzadeh M. Inhibitory effect of Crocus sativus (saffron) on histamine (H1) receptors of guinea pig tracheal chains. Pharmazie 2010; 65:300-305.
17. Boskabady MH, Rahbardar MG, Jafari Z. The effect of safranal on histamine (H(1)) receptors of guinea pig tracheal chains. Fitoterapia 2011; 82:162-167.
18.Nakisa N, Rahbardar MG. Action mechanisms of antirheumatic herbal medicines. In: Toumi H, editor. Rheumatoid Arthritis: IntechOpen; 2021.
19. Rajabian F, Mehri S, Razavi BM, Khajavi Rad A, Ghasemzadeh Rahbardar M, Hosseinzadeh H. Effect of trans-sodium crocetinate on contrast-induced cytotoxicity in HEK-293 cells. Iran J Basic Med Sci 2023; 26:148-156.
20.Rahbardar MG, Hosseinzadeh H. Mechanisms of action of herbal antidepressants. In: Martin CR, Hunter L-A, Patel VB, Preedy VR, Rajendram R, editors. The Neuroscience of Depression: Academic Press; 2021. p. 503-518.
21. Mohammadzadeh L, Ghasemzadeh Rahbardar M, Razavi BM, Hosseinzadeh H. Crocin protects malathion-induced striatal biochemical deficits by inhibiting apoptosis and increasing α-synuclein in rats’ striatum. J Mol Neurosci 2022; 72:983-993.
22. Bedrood Z, Masjedi E, Vahdati Hassani F, Ghasemzadeh Rahbardar M, Hosseinzadeh H, Abnous K, et al. Evaluation the effect of crocin on bisphenol A-induced memory impairment in rats: Role of ERK, CaMKII, and CREB proteins in hippocampus. North Khorasan Univ Medl Sci J 2023; 14:63-74.
23. Hosseinzadeh H, Sadeghnia HR, Ziaee T, Danaee A. Protective effect of aqueous saffron extract (Crocus sativus L.) and crocin, its active constituent, on renal ischemia-reperfusion-induced oxidative damage in rats. J Pharm Pharm Sci 2005; 8:387-393.
24. Çelik H, Kandemir FM, Caglayan C, Özdemir S, Çomaklı S, Kucukler S, et al. Neuroprotective effect of rutin against colistin-induced oxidative stress, inflammation and apoptosis in rat brain associated with the CREB/BDNF expressions. Mol Biol Rep 2020; 47:2023-2034.
25. Rezaee-Khorasany A, Razavi BM, Taghiabadi E, Tabatabaei Yazdi A, Hosseinzadeh H. Effect of crocin, an active saffron constituent, on ethanol toxicity in the rat: histopathological and biochemical studies. Iran J Basic Med Sci 2020; 23:51-62.
26. Mihara M, Uchiyama M. Determination of malonaldehyde precursor in tissues by thiobarbituric acid test. Anal Biochem 1978; 86:271-278.
27. Rahbardar MG, Eisvand F, Rameshrad M, Razavi BM, Hosseinzadeh H. In vivo and in vitro protective effects of rosmarinic acid against doxorubicin-induced cardiotoxicity. Nutr Cancer 2022; 74:747-760.
28. Moron MS, Depierre JW, Mannervik B. Levels of glutathione, glutathione reductase and glutathione S-transferase activities in rat lung and liver. Biochim Biophys Acta 1979; 582:67-78.
29. Ghasemzadeh Rahbardar M, Razavi BM, Hosseinzadeh H. Investigating the ameliorative effect of alpha-mangostin on development and existing pain in a rat model of neuropathic pain. Phytother Res 2020; 34:3211-3225.
30. Hartzell JD, Neff R, Ake J, Howard R, Olson S, Paolino K, et al. Nephrotoxicity associated with intravenous colistin (colistimethate sodium) treatment at a tertiary care medical center. Clin Infect Dis 2009; 48:1724-1728.
31. Edrees NE, Galal AAA, Abdel Monaem AR, Beheiry RR, Metwally MMM. Curcumin alleviates colistin-induced nephrotoxicity and neurotoxicity in rats via attenuation of oxidative stress, inflammation and apoptosis. Chem Biol Interact 2018; 294:56-64.
32. Nasrullah MZ, Eljaaly K, Neamatallah T, Fahmy UA, Alamoudi AJ, Bakhsh HT, et al. Omeprazole prevents colistin-induced nephrotoxicity in rats: Emphasis on oxidative stress, inflammation, apoptosis and colistin accumulation in kidneys. Pharmaceuticals 2022; 15:782.
33. Abou-Hany HO, Atef H, Said E, Elkashef HA, Salem HA. Crocin mediated amelioration of oxidative burden and inflammatory cascade suppresses diabetic nephropathy progression in diabetic rats. Chem Biol Interact 2018; 284:90-100.
34. Naghizadeh B, Mansouri SMT, Mashhadian NV. Crocin attenuates cisplatin-induced renal oxidative stress in rats. Food Chem Toxicol 2010; 48:2650-2655.
35. Canakci E, Karatas A, Coskun I, Benli E, Altinbas A, Akcay Celik M, et al. Investigation of the nephroprotective effect of dexmedetomidine on colistin-induced nephrotoxicity in rats. Bratisl Lek Listy 2022; 123:579-584.
36. Altinoz E, Oner Z, Elbe H, Cigremis Y, Turkoz Y. Protective effects of saffron (its active constituent, crocin) on nephropathy in streptozotocin-induced diabetic rats. Hum Exp Toxicol 2015; 34:127-134.
37. Parmar G, Mistry K, Gang S. Correlation of serum albumin and creatinine with oxidative stress markers in patients having nephrotic syndrome Int J Pharm Pharm Sci 2021; 13:20-24.
38. Hanedan B, Ozkaraca M, Kirbas A, Kandemir FM, Aktas MS, Kilic K, et al. Investigation of the effects of hesperidin and chrysin on renal injury induced by colistin in rats. Biomed Pharmacother 2018; 108:1607-1616.
39. Erdemli ME, Gul M, Altinoz E, Zayman E, Aksungur Z, Bag HG. The protective role of crocin in tartrazine induced nephrotoxicity in Wistar rats. Biomed Pharmacother 2017; 96:930-935.
40. Hassan MH, Bahashawan SA, Abdelghany TM, Abd‐Allah GM, Ghobara MM. Crocin abrogates carbon tetrachloride‐induced renal toxicity in rats via modulation of metabolizing enzymes and diminution of oxidative stress, apoptosis, and inflammatory cytokines. J Biochem Mol Toxicol 2015; 29:330-339.
41. Chen X, Wei W, Li Y, Huang J, Ci X. Hesperetin relieves cisplatin-induced acute kidney injury by mitigating oxidative stress, inflammation and apoptosis. Chem Biol Interact 2019; 308:269-278.
42. Karanovic D, Mihailovic‐Stanojevic N, Miloradovic Z, Ivanov M, Vajic UJ, Grujic‐Milanovic J, et al. Olive leaf extract attenuates adriamycin‐induced focal segmental glomerulosclerosis in spontaneously hypertensive rats via suppression of oxidative stress, hyperlipidemia, and fibrosis. Phytother Res 2021; 35:1534-1545.
43. Khan SR. Reactive oxygen species, inflammation and calcium oxalate nephrolithiasis. Transl Androl Urol 2014; 3:256-276.
44. Arisha SM. Effect of arabic gum aqueous extract on histological, ultrastructural, immunohistochemical and biochemical changes on colistin-induced nephropathy in male Albino rats. Egypt Acad J Biol Sci 2020; 12:23-44.
45. Hussain MA, Abogresha NM, AbdelKader G, Hassan R, Abdelaziz EZ, Greish SM. Anti-oxidant and anti-inflammatory effects of crocin ameliorate doxorubicin-induced nephrotoxicity in rats. Oxid Med Cell Longev 2021; 2021:8841726.